ANTIPSYCHOTIC TREATMENT OF SCHIZOPHRENIASeminar on the Manifestation of the Disease, Prevalence in Society, and Treatment by Antipsychotics

BY OLIVIA BERAN

A BEAUTIFUL MIND

OVERVIEW OF PRESENTATION MATERIAL

Definition Early Years General Causes Schizophrenia in the World Context Burden Symptoms Treatment

Typical Antipsychotics Atypical Antipsychotics

Selecting an Antipsychotic Assigned Reading Reading Questions

DEFINITION “Schizophrenia is a mental disorder

characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social or occupational dysfunction.”

Resource: "Schizophrenia." Wikipedia. Wikipedia, n.d. Web. 6 Apr 2011. <http://en.wikipedia.org/wiki/Schizophrenia>.

Embroidered cloth by

schizophrenia patient

THE EARLY YEARS OF SCHIZOPHRENIA

First described by Emil Kraeplin in 1896 Separated from

manic-depressive illness

“Dementia praecox” syndrome

“Schizophrenia” introduced by Eugen Bleuler in 1911

GENERAL CAUSES OF SCHIZOPHRENIA

Behaves epidemiologically like other complex diseases

Although, genetic factors neither necessary nor sufficient

Therefore, gene + environmental interactions schizophrenia

GENERAL CAUSES CONTINUED

Environmental risk factors: Season of birth Adverse rearing environments Urban life stresses during upbringing Cannabis use Stress in daily life Minority position

SCHIZOPHRENIA IN THE WORLD CONTEXT

Schizophrenia in an industrialized country vs. developing country Consider the World Health Organization

“Determinants of Outcome of Severe Mental Disorders” Study

Percentage of patients in full remission at the 2 year mark

63% in developing countries 37% in developed countries Explanation?

RATES OF SCHIZOPHRENIA BY COUNTRY PER 100,000 INHABITANTS

Resource: "Schizophrenia." Wikipedia. Wikipedia, n.d. Web. 6 Apr 2011. <http://en.wikipedia.org/wiki/Schizophrenia>.

BURDEN OF SCHIZOPHRENIA

Direct effects Care costs

Indirect effects Loss of productivity Disability and premature death Burden on caregivers Legal problems and violence

BURDEN CONTINUED

Disability and premature death 2001 World Health Report

8th leading cause of disability-adjusted life years worldwide

Reduces a person’s life span by 10 years 30% of schizophrenia patients attempt suicide at

least once in their lifetime About 10% of patients die by suicide

Cost Psychotic disorders = most expensive mental

illnesses in terms of costs of care/patient 1.5% (UK), 2% (the Netherlands, France), and

2.5% (USA) of national health expenditures

SYMPTOMS OF SCHIZOPHRENIA

Positive symptoms: Delusions Hallucinations Thought/reality disorders

Negative symptoms: Poverty of speech Lack of motivation Apathy Inability to express emotions

Cognitive deficits Alterations of attention, working memory, and

executive functions Positive symptoms < negative symptoms

TREATMENT OF SCHIZOPHRENIA

Medications Typical vs. atypical antipsychotics

Psychosocial interventions Rehabilitation

TYPICAL ANTIPSYCHOTICS

Early 1950s: discovery of chlorpromazine

Pros of chlorpromazine: Effective in treatment of positive symptoms Aids in prevention of psychotic relapses

Cons of chlorpromazine: Persistent symptoms Modest improvement of negative and cognitive

symptoms Acute (e.g. extra pyramidal side-effects [EPS])

and chronic side effects (e.g. tardive dyskinesia [TD])

HOW DO TYPICAL ANTIPSYCHOTICS WORK?

1976: Two studies confirm that neuroleptics altered dopamine (DA) turnover

HOW DO TYPICAL ANTIPSYCHOTICS WORK? CONTINUED

This DA hypothesis guided neurobiological research of Schizophrenia for 30 years

ATYPICAL ANTIPSYCHOTICS

Produce significantly fewer EPS and carry a lower risk of TD

Differ from typicals in mechanism of action, although atypicals do not all share the same mechanism

Prototype of atypical agents = clozapine

HOW DO ATYPICAL ANTIPSYCHOTICS WORK?

Serotonin (5-HT-)-receptor-based mechanisms postulated to play critical role in action of atypical antipsychotics

HOW DO ATYPICAL ANTIPSYCHOTICS WORK? CONTINUED

TYPICAL VS. ATYPICAL ANTIPSYCHOTICS

Major difference between these two classes is due to the potent 5-HT2A receptor antagonism + weak D2 receptor antagonism of clozapine and other atypicals from first generation typicals

In addition, while all second-generation antipsychotics work via dopamine and serotonin receptors, each is characterized by a unique pharmacological characteristics, most notably side effects

CLOZAPINE Manufactured in 1959 and first marketed in early

1960s Withdrawn from market in mid-1970s after Finnish

incident + agranulocytosis Even so, clozapine reintroduced so as to treat

people… Resistant to typical neuroleptics Compliant with blood monitoring

Improves delusions and hallucinations Reduces the risk of suicide Increases cortical dopamine (DA) and acetylcholine

release Various effects on glutamatergic system Main clinical advantage = nil incidence of EPS

EXTENSION OF ATYPICAL

Originally, atypical = clozapine Extended to include characteristics common

to recently developed antipsychotic drugs Absence of hyperprolactinemia Greater efficacy in treating (+) and (-) symptoms Absence of TD or dystonia after chronic

administration

RISPERIDONE

Benzisoxazolic derivative with strong blocking affect on the D2 and 5-HT2 receptors

Stronger effect than haloperidol (= 1st generation APD) but only when administered in doses > 8 mg/day

OLANZAPINE

Tienobenzodiazepine Affinity for the following binding sites:

Dopamine (D1 – D4) Serotonergics (5-HT2,3,6) Muscarinics (sub-types 1 – 5) Adrenergics (alpha2) Histaminergics

Greater effect than haloperidol when administered at daily dose of 7.5 – 20 mg

QUETIAPINE

New antipsychotic Structurally related to clozapine but no need

for blood monitoring Predominant affinity for 5-HT2 in comparison

with D2 Low incidence of EPS (less than 10%)

ZIPRASIDONE

Benzotiazolilpiperazine More affinity for 5-HT2 than D2 receptor Provokes less EPS than conventional/typical

antipsychotics

ARIPIPRAZOLE

One of the newest antipsychotics Acts as an antagonist as well as an agonist Lower incidence of EPS as well

WHICH DRUG IS RIGHT FOR ME?

Consider a young, highly agitated young man of normal weight who is highly agitated and has a history of treatment resistance Clozapine

Low risk for drug-induced obesity Side effect of sedation Failure to respond to other antipsychotics

Consider a slightly overweight middle-aged woman who is stable but needs chronic treatment Risperidone

Less risk of weight gain Ziprasidone

If patient experiences serious depression

RESOURCES De Oliveira, I.R., and M.F. Juruena. "Treatment of

psychosis: 30 years of progress." Journal of Clinical Pharmacy and Therapeutics 31.6 (2006): 523-34. Web. 5 Feb 2011.

Roessler, Wulf, Hans Joachim Salize, Jim van Os, and Anita Riecher-Roessler. "Size of burden of schizophrenia and psychotic disorders." European Neuropsychopharmacology 15. (2005): 399-409. Web. 5 Feb 2011.

"Schizophrenia." Wikipedia. Wikipedia, n.d. Web. 6 Apr 2011. <http://en.wikipedia.org/wiki/Schizophrenia>.

Tamminga, Carol. "Similarities and Differences Among Antipsychotics." Journal of Clinical Psychiatry 64. (2003): 7-10. Web. 6 Apr 2011.

ASSIGNED READING

De Oliveira, I.R., and M.F. Juruena. "Treatment of psychosis: 30 years of progress." Journal of Clinical Pharmacy and Therapeutics 31.6 (2006): 523-34. Web. 5 Feb 2011. Only read p. 523 – 527

READING QUESTIONS

In 1980, a distinction was made between two types of schizophrenia. Define type I schizophrenia and type II schizophrenia, as well as the types of symptoms usually experienced within each type of the disease.

What was the first typical antipsychotic developed?

Define atypical antipsychotic drugs. What was the first atypical antipsychotic

developed?